Kawasaki Disease (KD) is an increasingly recognized, potentially fatal acute vasculitis of young children that may lead to coronary artery aneurysm (CAA) formation. The goal of my research is to understand the pathogenesis of KD. During the past 3 years, we showed that there is a marked infiltration of the upper respiratory tract and CAA by IgA plasma cells in acute KD, strongly suggesting a respiratory portal of entry of the KD agent. We demonstrated that the IgA response in the KD arterial wall is oligoclonal, and thus antigen-driven. We found that CD8 T lymphocytes and macrophages infiltrate CAA in acute KD, consistent with an immune response to an intracellular pathogen such as a virus. We also showed that macrophages in acute KD CAA produce matrix metalloproteinase-9, which can contribute to CAA formation by disrupting extracellular matrix. We hypothesize that during acute KD, macrophages engulf and are activated by the KD agent and/or produce proteins that result in pathogenesis. In this proposal, we provide preliminary data indicating that a synthetic KD antibody, which we generated from a prevalent IgA gene sequence in acute KD arterial tissue, binds to an antigen expressed by macrophages in acute KD tissues. Other preliminary data indicate extensive angiogenesis is ongoing in areas of macrophage infiltration in acute KD CAA. Collectively, these data indicate an important role of macrophages in KD pathogenesis. We will 1) determine whether an imbalance of angiogenic mediators secreted by macrophages contributes to KD vasculopathy, 2) generate synthetic antibodies and determine if they recognize antigens in KD tissues, and 3) identify the antigen reacting with the KD synthetic antibody. These studies will provide insight into the role of macrophages in the pathogenesis of KD, will identify important antigen-antibody interactions in acute KD, and may lead to improved diagnosis and treatment of this potentially devastating childhood illness.